Rheumatoid arthritis is an inflammatory disease characterized by the intense infiltration of the synovium with a variety of mononuclear cells, including CD4+ T cells. Awareness of the likely role of these cells and their secreted products in rheumatoid inflammation has suggested new forms of treatment using specific monoclonal antibodies (mAb) or other biologic agents. Despite a number of therapeutic trials, however, little mechanistic understanding of the biologic impact of these interventions has been developed. Based upon a dissection of the biologic effects of a mAb to ICAM-1 (CD54), a number of hypotheses have been generated about the impact of this particular therapeutic intervention. Specifically, anti- ICAM-1 therapy appears to alter the circulatory patterns of Th1-like T cells during the administration of the mAb, and leads to long-lasting T cell anergy that persists after therapy is completed and correlates with improvement in disease activity. Moreover, profiles of cytokine mRNA levels in peripheral blood mononuclear cells before, during and after therapy also appear to correlate with outcome. Based upon these preliminary results, experiments will be carried out in additional patients treated with anti-ICAM-1 mAb, and a non-depleting mAb to CD4, to determine whether clinical benefit results from the induction of T cell anergy and to investigate the basis of the alteration in T cell function. Moreover, patients treated with a mAb to TNFalpha will be examined to determine whether changes in T cell function also occur that correlate with improvement in disease activity. Specifically, the proposed experiments will determine whether treatment with a non-depleting anti-CD4 mAb, as well as with anti-ICAM-1, induces anergy of memory T cells, and whether the persistence of the anergic state correlates with clinical benefit. In addition, alterations in T cell function owing to therapy with the anti-TNFalpha mAb will also be examined. Finally, experiments will be carried out to determine whether analysis of cytokine mRNA levels in peripheral blood mononuclear cell subsets can predict the response to therapy with mAb to CD4, ICAM-1 or TNFalpha, and whether therapy related changes in cytokine mRNA levels might correlate with or predict clinical benefit. These studies should form the foundation of a mechanistic understanding of the immunologic impact of these specific interventions in patients with rheumatoid arthritis.
